W98: Clinical Trials: The Industry Perspective

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W98 Clinical Trials The Industry Perspective

• Kathi Durdon, MA, CCRPDirector, Clinical Trials
  OfficeSUNY Upstate Medical UniversitySyracuse,
  NY

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Objectives

• Overview Basics of Clinical Research
• Review of Regulatory Requirements
• Review Site Selection Criteria
• Review HIPAA Implications on Conduct of Clinical
  Research
• Summary of Industry Expectations

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Audience Survey

• Who Do You Work For?
• Industry/Sponsor
• Clinical Research Organization
• Site
• Other?

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Basics of Clinical Research
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What are Clinical Trials?

• Research study in human volunteers which answer
  specific health questions.
• Carefully conducted trials are the safest and
  fastest way to find treatments that work in
  people, and new ways to improve health.

FDA Basic Questions
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Different Kinds of Trials

• New treatments new combinations of drugs, new
  approaches to surgery or therapy
• Prevention trials prevent disease - medicines,
  vitamins, vaccines, minerals, or lifestyle
  changes
• Diagnostic trials better tests/procedures
• Screening trials best way to detect certain
  diseases or health conditions
• Quality of Life trials (Supportive Care)
  explore/ measure ways to improve comfort/quality
  of life for individuals with a chronic illness

FDA Basic Questions
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Sponsored Clinical Trials - 2003
Number of Sponsored Trials
NIH Other Industry
University/ Fed Agency Organization
TRIAL SPONSORS
Fda Consumer Magazine http//www.fda.gov/fdac/fea
tures/2003/503_trial.html
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Where are Drugs Developed?
Source National Survey, 2004Charlton Research
Company for Research! America
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Where are Drugs Developed?

• NIH reported to Congress in 2001 that it found a
  significant government investment in only 4 of 47
  medicines with sales of 500 million or more

PhRMA What goes into the cost of prescription
drugs
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Translating Discovery into Practice

• Government NIH-funded academic scientists do a
  terrific job in advancing basic knowledge about
  biology and disease. Their work improves our
  understanding of diseases. But pharmaceutical
  company scientists lead the way in translating
  basic science into practical medicines that help
  and heal patients.

PhRMA What goes into the cost of prescription
drugs
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Phases of Clinical Research

• Discovery
• Pre-clinical
• IND Submission
• Phase I
• Phase II
• Phase III
• FDA Review/Approval
• Phase IV Post-marketing Surveillance

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Discovery of Leads Candidates

• New compounds that may become the new medicine
• Millions of compounds are screened per year
• Vast majority fail at this stage

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Average Number of Compounds Completed During
Discovery
Source Parexels Pharmaceutical RD Statistical
Sourcebook, 2001
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Pre-clinical

• Extensive toxicological tests and animal studies
• Determine whether drug is likely to be safe and
  effective in humans

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Investigational New Drug (IND)

• Application includes
• All pre-clinical data
• Manufacturing information
• Approval allows drug to be tested in humans
• 30-day review
• Progress reports filed annually

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Phase I

• Assess drug safety
• Small number of healthy volunteers
• Determine what happens to the drug in the human
  body--how it is absorbed, metabolized, and
  excreted
• Investigates side effects that occur as dosage
  levels are increased
• Typically takes several months

CenterWatch Patient Resources
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Phase II

• Assess efficacy
• About 100-300 subjects w/targeted disease
• Most are randomized trials one group of subjects
  receive the experimental drug, while second
  "control" group receive standard treatment or
  placebo
• Often studies are "blinded, neither patients nor
  researchers know who is getting the experimental
  drug
• Can last 3 months - two years

CenterWatch Patient Resources
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Phase III

• Large-scale testing (1000-3000)
• Provides more thorough understanding
  effectiveness, benefits, and the range of
  possible adverse reactions
• Most are randomized and blinded trials
• Typically last several years
• Once successfully completed, pharmaceutical
  company can request FDA approval for marketing
  the drug

CenterWatch Patient Resources
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Phase IV

• Studies often compare a drug with other drugs
  already in the market
• Studies are often designed to monitor a drug's
  long-term effectiveness and impact on a patient's
  quality of life
• Many studies determine the cost-effectiveness of
  a drug therapy relative to other traditional and
  new therapies

CenterWatch Patient Resources
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Testing in Humans
FDA Testing in Humans
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Drug Development Timeline
Creation Lab Testing 2-4 Years IND
Submission 2-3 Months Human Testing 3-7
Years NDA Preparation 6-12 Months FDA
Approval 6-12 Months Post-Marketing
Testing Ongoing
James Bolognese, Biostatistician, Merck Research
Laboratories
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Source Pharmaceutical Research and
Manufacturers of America, based on data from
Center for the Study of Drug Development, Tufts
University, 1995.
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RD Investment

• PhRMA reported biotech pharma research members
  recorded 38.8 billion in RD on medicines in
  2004 (up from 34.5 billion in 2003).
• 30.6 billion in US / 8.2 billion abroad
• 1980 RD investment 2 billion

PhRMA Press Release, February 18,
2005www.phrma.org/mediaroom/press/releases/18.02.
2005.1128.cfm
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RD Investment

• One new medication cost to develop 500 million

Boston Consulting Group
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(No Transcript)
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Trends in Research Spending
Indexed Growth (1993 100)
Year
FDA/AAMC Drug Development Science Obstacles and
Opportunities for Collaboration Among Academia,
Industry and Government
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Trends in Drug Biological Product Submissions
to FDA
Submissions to FDA
Year
NME New Molecular Entity BLA Biologic License
Application
FDA/AAMC Drug Development Science Obstacles and
Opportunities for Collaboration Among Academia,
Industry and Government
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Industry Leading the Way

• In the last two years
• Over 100 new drugs became available
• 1000 new medicines in development
• Employs over 250,000 in the US
• Research spending has nearly doubled every 5
  years since 1970
• Average cost spent on prescription drugs 59
  cents

PhRma Facts about the US Pharmaceutical Industry
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Regulatory Overview
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Nuremberg Code - 1949

• In the fall of 1943, the United States, Great
  Britain, and the Soviet Union agreed that, once
  victorious, they would prosecute individuals
  among the enemy who might have violated
  international law during the war. On August 8,
  1945--exactly three months after V.E. Day and two
  days after the bombing of  Hiroshima--representati
  ves of the American, British, French, and Soviet
  governments officially established the
  International Military Tribunal in Nuremberg,
  Germany.

Trials of War Criminals before the Nuremberg
Military Tribunals under Control Council Law No.
10, vol 2, pp 181-182, Washington, DC
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Nuremberg Code - 1949

• Voluntary consent of human subjects is absolutely
  essential
• Experiment should yield fruitful results for the
  good of society, unprocurable by other methods or
  means of study
• Designed and based on results of animal
  experimentation
• Avoid all unnecessary physical and mental
  suffering and injury

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Nuremberg Code -1949

• Degree of risk taken should never exceed that
  determined by the humanitarian importance of the
  program to be solved
• Proper preparations, facilities provided to
  protect experimental subject
• Conducted only by scientifically qualified
  persons
• Subject may end participation in experiment at
  any time

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Declaration of Helsinki - 1964

• A statement of ethical principles to provide
  guidance to physicians and other participants in
  medical research involving human subjects.
  Medical research involving human subjects
  includes research on identifiable human material
  or identifiable data.

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Belmont Report - 1979

• Basic Ethical Principles
• Respect for Persons
• Beneficence
• Justice
• Applications
• Informed Consent
• Assessment of Risk and Benefits
• Selection of Subjects

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Tuskegee 1932 - 1972

• For forty years between 1932 and 1972, the U.S.
  Public Health Service (PHS) conducted an
  experiment on 399 black men in the late stages of
  syphilis. These men, for the most part illiterate
  sharecroppers from one of the poorest counties in
  Alabama, were never told what disease they were
  suffering from or of its seriousness. Informed
  that they were being treated for bad blood,1
  their doctors had no intention of curing them of
  syphilis at all. The data for the experiment was
  to be collected from autopsies of the men, and
  they were thus deliberately left to degenerate
  under the ravages of tertiary syphilis

Bad Blood The Tuskegee Syphilis Experiment,
James H. Jones, (New York Free Press, 1993).
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Legislative Reaction
K. Zoon, The Regulation of Drug and Biological
Products, 2001
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Regulations/Historical Overview
Source Milestones in U.S. Food and Drug Law
History
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(No Transcript)
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Source Milestones in U.S. Food and Drug Law
History
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ICH - 1994

• International Conference of Harmonization of
  Technical Requirements for Registration of
  Pharmaceuticals for Human Use (ICH)
• Agreed definitions, terminology, procedures to
  ensure uniform Good Clinical Practice (GCP)

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E6 Good Clinical Practice

• Conducted in accordance with ethical principles
  having origin in the Declaration of Helsinki.
• Guideline for the international ethical and
  scientific quality standard for designing,
  conducting, recording and reporting trials that
  involve the participation of human subjects.

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Principles of ICH GCP

• Anticipated benefits justify risks
• Rights, safety and well-being of trial subjects
  are the most important consideration
• Conducted in compliance with clear, detailed
  protocol which has received approval by IRB/IEC
• Freely given informed consent

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Code of Federal Regulations

• The Code of Federal Regulations (CFR) is the
  codification of the general and permanent rules
  published in the Federal Register by the
  executive departments and agencies of the Federal
  Government.
• http//www.gpoaccess.gov/cfr/

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Title 21 Food and Drugs

• Section
• 50 Protection of Human Subjects
• 54 Financial Disclosure by Investigators
• 56 Institutional Review Boards
• 312 Investigational New Drug Application

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Site Selection Criteria
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Sponsor/CRO/Site Relationship

• Communication
• Direct Contacts
• Prompt Response
• Understand Perspectives
• Dont Assume

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Site Selection Criteria

• Experience
• Trained Staff
• Space
• Subjects
• Protected Time
• Local IRB / Central IRB
• Agreement / Budget Processing Timelines

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Investing in a Country

• Access to skilled workforce/scientists
• Quality of science in the country
  Academia/Universities/Biotech clusters
• Industry/Government partnerships
• Fiscal/Economic climate

Gail H. Cassell, Ph.D., Vice President,
Scientific Affairs Eli Lilly and Company
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Site Questionnaire

• Verify of pts. seen in _ of months
• Competing study?
• Review of standard therapy
• Recruitment practices
• Facilities
• Additional services required
• Equipment

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Pre-study Visit

• Obtain documents necessary to proceed with
  prestudy visit (e.g., confidentiality agreement,
  curriculum vitae)
• Develop an agenda
• Send documents necessary for prestudy visit to
  the site (e.g., protocol, Investigator's
  Brochure)
• Confirm appointment and ensure necessary
  personnel are available

ACRP
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Pre-study Visit

• Explain Investigator's Brochure to
  investigator/study staff
• Explain protocol, study goals, methodology,
  regulatory obligations, and sponsor/CRO
  requirements to investigator/study staff
• Assess investigator/study staff
• Document and communicate pre-study visit findings
  internally

ACRP
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Study Initiation

• Conduct investigator's meeting(s)
• Send study supplies to site
• Initiate shipment of investigational product
• Confirm appointment and ensure necessary
  personnel are available
• Train site personnel on sponsor/CRO and
  regulatory requirements for study conduct

ACRP
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Study Monitoring

• Identify items for review
• Confirm appointment and ensure necessary
  personnel are available
• Assemble necessary documents and monitoring tools
  (e.g., subject enrollment status sheets,
  monitoring guidelines)
• Ensure adequacy of study supplies and
  investigational product at site
• Monitor and evaluate subject enrollment

ACRP
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Monitoring Visit

• Assess protocol adherence
• Ensure that critical studies are conducted in
  accordance with local, state, federal, and
  appropriate regulatory regulations (e.g., IRB/IEC
  approval, informed consent, laboratory
  certification)
• Ensure that informed consent process is conducted
  according to Good Clinical Practice (GCP)

ACRP
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Monitoring Visit

• Identify and communicate subject safety issues to
  appropriate staff (e.g., laboratory
  abnormalities)
• Reconcile investigational product accountability
• Review study files and regulatory documents at
  site for completeness and accuracy (e.g., FDA
  form 1572, sponsor/CRO correspondence, informed
  consent form)

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Monitoring Visit

• Review CRFs and source documents for completeness
  and consistency
• Identify and report significant adverse events to
  appropriate staff
• Confirm subjects' investigational product
  compliance
• Identify study site deficiencies, provide
  continuing training, and implement corrective
  action when necessary
• Assess enrollment issues

ACRP
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Monitoring Visit

• Prepare the monitoring visit report
• Prepare the monitoring visit follow-up letter to
  the site
• Report problems to appropriate in-house authority
  
• Identify potential fraud and misconduct

ACRP
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HIPAA Implications
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HIPAA

• Health Insurance Portability and Accountability
  Act of 1996
• HIPAA covers insurance portability fraud
  enforcement (accountability) and administrative
  simplification

Lawrence H. Muhlbaier, Ph.D. HIPAA Training
Handbook for Researchers
60
HIPAA

• Portability ensures that individuals moving
  from one health plan to another will have
  continuity of coverage/not denied coverage under
  preexisting condition clauses
• Accountability significantly increases the
  federal governments fraud enforcement authority

Lawrence H. Muhlbaier, Ph.D. HIPAA Training
Handbook for Researchers
61
Administration Simplification!?

• Privacy Rule protects individuals right to
  control access to and disclosure of their
  protected health information (PHI).
• Security established to complement privacy
  measures.

Lawrence H. Muhlbaier, Ph.D. HIPAA Training
Handbook for Researchers
62
Research Under HIPAA

• Almost all research other than some Phase I
  studies involving healthy subjects.
• HIPAA covers all research activities that use
  individually identifiable (names, addresses,
  dates, phone/fax, etc.) health information about
  humans

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Coverage

• Covered Entities
• Health Care Providers (Physicians, Hospitals)
• Health Care Plans (Insurers, HMOs, Medicare)
• Health Care Clearinghouses (transmit data)
• Business Associates use protected health
  information (PHI) for or on behalf of covered
  entities

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Research Under HIPAA

• Use happens within a health care
  organization/covered entity
• Disclosure information is given to someone who
  is not part of the organizations work force
• User must use Notice of Privacy Practices

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Impact on Research

• Sponsors are generally not a Covered Entity or
  Business Associate
• Most entities through which sponsors conduct
  human-subject research are covered entities
• Sponsors cannot contact potential subjects but
  the covered entity can

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Impact on Research

• Extended Informed Consent Process
• Indirect Subject Recruitment
• Variations in Interpretation Leads to Confusion
• Delays

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Industry Expectations
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Barriers to Success

• Number of Investigators Decreasing
• Who Does the Training?
• Employee Turnover
• Regulatory Delays

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Drivers of Innovation

• Market-based pricing
• Intellectual property protection
• Sustained public support for basic research and
  policy environment
• Predictable, expeditious regulatory climate based
  upon sound science and innovative leadership

Gail H. Cassell, Ph.D., Vice President,
Scientific Affairs Eli Lilly and Company
70
Helpful Links

• CFR http//www.gpoaccess.gov/cfr/
• FDA www.fda.gov
• PhRMA http//www.phrma.org/
• CenterWatch http//www.centerwatch.com/index.htm
  l
• Sponsor Web Pages